Alzheimer's disease (AD) is associated with degenerative changes and loss of various populations of neurons in the brain. Since neurotrophic factors regulate neuronal survival and maintenance of function, such factors may provide avenues for the development of effective treatment for AD. By preventing or attenuating neuronal degeneration, neurotrophic factors may slow down or stop the progression of the disease and associated cognitive disturbances. Based on its ability to prevent degenerative changes of cholinergic neurons induced by experimental lesions in rats and monkeys, nerve growth factor (NGF) is presently under consideration as experimental treatment for AD. One specific aim of this application, related to NGF's long-term effects and the feasibility of slow-releasing implants, will provide additional information valuable for clinical use of NGF. However, the value of NGF in the treatment of AD is limited by its specificity for forebrain cholinergic neurons. The recent discovery of homologs of NGF, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), established the family of neurotrophins. These neurotrophins affect a variety of peripheral and central neurons and their effects overlap for some neuronal populations but differ for others. Recent findings, which provide the basis for this application, indicate that posttranslational modifications of the neurotrophins influence their biological activities and their specificity to act on subsets of neuronal populations. Therefore, it is proposed to prepare modified molecular forms of the neurotrophins either by recombinant expression or by specific protease treatment. Biological effects of these modified neurotrophins will then be characterized initially in neurotrophin receptor assays and in cell culture assays.Biologically active modified neurotrophins selected by the in vitro assays will then be tested in vivo in rat brain lesion models mimicking selective degenerative changes occurring in AD brains. These modified neurotrophins will be tested for their ability to counteract molecular, morphological, and behavioral deficits induced by the experimental lesions. Additional studies, using immunohistochemistry and retrograde transport methodologies, aim at identifying previously unknown neurotrophin-responsive cell populations. In summary, this program project aims at identifying modified neurotrophins able to specifically affect survival and function of neuronal populations degenerating in Alzheimer's disease. It is hoped that the studies will lead to the discovery of modified neurotrophins with either restricted or broadened biological specificity when compared with their natural counterparts and in the identification of molecules most promising for further development as therapeutics in Alzheimer's disease. The program project joins established academic and industrial scientists with a record of previous collaboration in the pharmacological exploitation of neurotrophic factors for developing effective treatment for AD and cognitive diseases.